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WO2003016307A1 - Agonistes de beta-3 adrenergiques - Google Patents

Agonistes de beta-3 adrenergiques Download PDF

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Publication number
WO2003016307A1
WO2003016307A1 PCT/US2002/021317 US0221317W WO03016307A1 WO 2003016307 A1 WO2003016307 A1 WO 2003016307A1 US 0221317 W US0221317 W US 0221317W WO 03016307 A1 WO03016307 A1 WO 03016307A1
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WO
WIPO (PCT)
Prior art keywords
mmol
amine
compound
mixture
alkyl
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PCT/US2002/021317
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English (en)
Inventor
Jolie Anne Bastian
Britta Evers
Don Richard Finley
John Xiaoqiang He
Cynthia Darshini Jesudason
Rushad E. Karanjawala
Andrew Michael Ratz
Vincent Patrick Rocco
Gerd Ruehter
Daniel Jon Sall
Theo Schotten
Patrick Gianpietro Spinazze
Freddie Craig Stevens
William George Trankle
John Arnold Werner
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Eli Lilly And Company
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Priority to US10/486,867 priority Critical patent/US7208505B2/en
Priority to DE60215028T priority patent/DE60215028T2/de
Priority to JP2003521230A priority patent/JP2005501856A/ja
Priority to EP02752178A priority patent/EP1421078B1/fr
Publication of WO2003016307A1 publication Critical patent/WO2003016307A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is in the field of medicine, particularly in the treatment of Type 2 diabetes and obesity. More specifically, the present invention relates to ⁇ 3 adrenergic receptor agonists useful in the treatment of Type 2 diabetes and obesity.
  • Type 2 diabetes non-insulin dependent diabetes as well as obesity
  • Patient compliance is usually poor.
  • the problem is compounded by the fact that there are currently no approved medications that adequately treat either Type 2 diabetes or obesity.
  • the ⁇ 3 receptor which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the ⁇ i and ⁇ 2 receptor subtypes yet is considerably less abundant. Stimulation of the ⁇ i and ⁇ 2 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors.
  • An agonist that is selective for the ⁇ 3 receptor over the ⁇ ⁇ and ⁇ 2 receptors is, therefore, more desirable for treating Type 2 diabetes or obesity relative to a non-selective agonist.
  • the present invention relates to a compound of formula I:
  • a , A 2 and A 3 are carbon or nitrogen provided that only one of A , A 2 and A 3 can be nitrogen;
  • D is NR 8 , O or S;
  • Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring;
  • Rl and R 2 are independently H, halo, hydroxy, Ci -Cg alkyl, Ci -Cg alkoxy, Ci -
  • R 3 is H or C!-C 6 alkyl
  • R 4 forms a bond with X 2 or is H, cyano, Ci -Cg alkyl, CONR 9 R 9 or CO 2 R 9 ;
  • R5 forms a bond with X 2 or is H or Ci -Cg alkyl
  • R6 is independently at each occurrence halo, hydroxy, cyano, Ci -Cg alkyl, C1-C4 haloalkyl or Ci -Cg alkoxy;
  • R 8 forms a bond with X 2 or is H or Cj-Cg alkyl;
  • R 9 and R 1 ⁇ are independently at each occurrence H, Cj-Cg alkyl or phenyl; or when two R 9 or two R 1 ⁇ moieties are connected to the same nitrogen atom, then said R 9 or RIO moieties may combine with the nitrogen to which they are attached to form a pyrollidinyl, piperidinyl or hexamethyleneimino ring;
  • R 1 1 is cyano, CO 2 R 16 , CONR 16 R 16 , CONR 16 SO 2 R 16 , SO 2 R 16 , heterocycle or optionally substituted phenyl;
  • R 12 and R 13 are independently at each occurrence H or Ci -Cg alkyl
  • R 14 is hydrogen, CO R 17 , CONR 17 R 17 , SO 2 R 17 , SO NR 17 R 17 , optionally substituted phenyl or optionally substituted heterocycle, R 15 is cyano, NR 18 R 18 , NR 18 SO R 18 or OR 18 ; R 1 6, R 17 and R 18 are independently at each occurrence H, C 1 -Cg alkyl or phenyl; or when two R1° ⁇ or two R 17 or two R 18 moieties are connected to the same nitrogen atom, then said R 1 ⁇ or R 17 or R 1 moieties may combine with the nitrogen to which they are attached to form a pyrollidinyl, piperidinyl or hexamethyleneimino ring; n is 0, 1, 2 or 3; p is 1, 2 or 3;
  • X is absent or is OCH2 or SCH2;
  • X I is absent or is (CR 19 R 2 0) q ;
  • X 2 is absent or is CO, CONR 21 or NR 21 CO; q is 1, 2, 3, 4 or 5; R 1 and R 2 ⁇ are independently at each occurrence H or Ci -Cg alkyl; or R 1 and
  • R 2 ⁇ combine with the carbon to which they are both attached to form a C3-C7 carbocyclic ring; and R 21 is H or Ci -Cg alkyl; or a pharmaceutical salt thereof.
  • the present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I.
  • the pharmaceutical formulations of the present invention maybe adapted for use in treating Type 2 diabetes and obesity and for agonizing the ⁇ 3 receptor.
  • the present invention also relates to methods for treating Type 2 diabetes and obesity, as well as a method for agonizing the ⁇ 3 receptor employing a compound of formula I.
  • the present invention relates to a compound of formula I for use in treating Type 2 diabetes and obesity as well as a compound of formula I for use in agonizing the ⁇ 3 receptor.
  • the present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type 2 diabetes and obesity as a well as for agonizing the ⁇ 3 receptor.
  • halo represents fluoro, chloro, bromo, or iodo.
  • Cj-Cg alkyl represents a straight, branched or cyclic hydrocarbon moiety having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like.
  • Ci -C4 alkyl refers specifically to methyl, ethyl, n- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and cyclobutyl.
  • a "Ci -C4 haloalkyl” group is a Ci -C4 alkyl moiety substituted with up to six halo atoms, preferably one to three halo atoms. An example of a haloalkyl group is trifluoromethyl.
  • a "Ci -Cg alkoxy” group is a Ci -Cg alkyl moiety connected through an oxy linkage.
  • optionally substituted means an optional substitution of one to three, preferably one or two groups independently selected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, triazole, tetrazole, 4,5-dihydrothiazole, Ci -Cg alkyl,
  • NR 2 COR 23 NR 22 SO 2 R 23 , OCOR 23 , OCO 2 R 22 , OCONR 22 R 22 , SR 22 , SOR 23 , SO2R 23 and SO2(NR 22 R 22 ), where R 22 is independently at each occurrence H, Ci -Cg alkyl, phenyl or benzyl and R 23 is independently at each occurrence Ci -Cg alkyl, phenyl or benzyl.
  • heterocycle and “heterocyclic” represent a stable, saturated, partially unsaturated, fully unsaturated or aromatic 5 or 6 membered ring, said ring having from one to four heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen.
  • the heterocycle may be attached at any point which affords a stable structure.
  • heterocycles include 1,3-dioxolane, 4,5- dihydrooxazole, furan, imidazole, imidazohdine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione, oxazolidone, piperazme, piperidine, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole.
  • benzofused heterocycles include benzoxazole, benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, and indole. Further specific examples of benzofused and non-benzofused heterocycles are described below in the Preparations and Examples sections.
  • suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
  • the term "patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals.
  • Livestock animals are animals raised for food production. Ruminants or "cud-chewing" animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock.
  • Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese.
  • livestock include fish, shellfish and crustaceans raised in aquaculture.
  • exotic animals used in food production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches).
  • the preferred patient of treatment is a human.
  • treating and “treat”, as used herein, include their generally accepted meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.
  • preventing prevention of, “prophylaxis”, “prophylactic” and “prevent” are used herein interchangeably and refer to reducing the likelihood that the recipient of a compound of formula I will incur or develop any of the pathological conditions, or sequela thereof, described herein.
  • the term “effective amount” means an amount of a compound of formula I that is capable of treating conditions, or detrimental effects thereof, described herein or that is capable of agonizing the ⁇ 3 receptor.
  • selective ⁇ 3 receptor agonist means a compound that displays preferential agonism of the ⁇ 3 receptor over agonism of the ⁇ i or ⁇ 2 receptor.
  • ⁇ 3 selective compounds behave as agonists for the ⁇ 3 receptor at lower concentrations than that required for similar agonism at the ⁇ j and ⁇ 2 receptors.
  • a ⁇ 3 selective compound also includes compounds that behave as agonists for the ⁇ 3 receptor and as antagonists for the ⁇ i and ⁇ 2 receptors.
  • formulation as in pharmaceutical formulation, is intended to encompass a product comprising the active ingredient(s) (compound of fonnula I), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other non-human animals (as described above), each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • the compound of formula I may exist as a pharmaceutical base addition salt thereof.
  • Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.
  • the compound of formula I can also exist as a pharmaceutical acid addition salt.
  • Such salts include the salicylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-l,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,
  • Certain compounds of the invention are particularly interesting and are preferred.
  • the following listing sets out several groups of preferred compounds. It will be understood that each of the listings may be combined with other listings to create additional groups of preferred compounds.
  • a) the bond represented by a dashed line is a double bond; b) m is 0 or 1 ; c) m is 0; d) A 1 , A 2 and A 3 are carbon; e) D is NH; f) Het is at the ortho-position relative to X; g) Het is an optionally substituted 5-membered, non-benzofused ring; h) Het is selected from benzothiophene; furan; isoxazole; oxazole; pyrrole; tetrazole and thiophene; wherein said Het moieties are optionally substituted once with methyl, cyano, SO2NH2 or COCH3; i) Het is pyrrol- 1-yl; j) Het is thien-2-yl optionally substituted once with methyl, cyano, SO2NH2 or COCH 3 k) Het is thien-2-yl optionally substituted once with cyano, SO
  • R 2 is H, methyl, chloro or fluoro; s) R 2 is H or fluoro; t) R 2 is H; u) R 3 is H; v) R 4 is H; w) R5 forms a bond with X 2 ; x) R6 is cyano at each occurrence; y) R 7 is at the 6- or 7-position of the indole, benzofuran or benzothiophene ring system to which it is attached; z) R 7 is at the 7-position; aa) R 7 is H or CO2H; bb) R 7 is CHK ⁇ R 1 1 ; R 1 1 is tetrazole, CONR 16 R 16 or CO 2 R 16 ; and R 16 is independently H or Ci -C4 alkyl at each occurrence; cc) R 7 is CH2CH2R 1 !
  • R 1 i is CO2R 16 or CONR 1 6R 1 6 , and R 16 is independently H or Ci -C4 alkyl at each ccurrence; dd) R 7 is CH2CH2R 11 , R 11 is 1 ,2,3,4-tetrazole or phenyl substituted once with SO2NR R 2 , and R 22 is independently H or Ci -C4 alkyl at each occurrence; ee) R 7 is thienyl substituted once with CO2H or phenyl substituted once with CO 2 H; ff) R 7 is OCH 2 CONHSO 2 (C 1 -C 4 alkyl); OCH 2 CH 2 NHSO 2 (C 1 -C 4 alkyl);
  • the reaction of Scheme 1 may be carried out under conditions appreciated in the art for the amination of epoxides.
  • the epoxide of formula II maybe combined with an amine of formula III in a lower alcohol, dimethylformamide, dimethylsulfoxide, or acetone, preferably ethanol, isopropanol, n-butanol or t-butanol, at room temperature to the reflux temperature of the reaction mixture, preferably between 40°C - 90°C.
  • the reaction may also be carried out under conditions generally described in Atkins, et al., Tet. Let., 27:2451, 1986.
  • These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.
  • a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.
  • the compound of formula I may also be prepared via a Suzuki coupling reaction as shown in Scheme 2.
  • a compound of formula IV may be reacted with a compound of formula III as described above in Scheme 1.
  • the compound of formula N (an aryl halide) may then be reacted with a heteroaryl boronic acid, an aryl boronic ester, or an aryl boronic cyclic ester, preferably an aryl boronic acid, under conditions appreciated in the art for the coupling of aromatic halides with aryl boronic acids and their derivatives.
  • This coupling is known in the art generally as a Suzuki coupling.
  • an aryl triflate may also be employed in the present Suzuki coupling as an alternative to employing an aryl halide.
  • epoxide starting materials employed in Schemes 1 and 2 may be prepared by techniques recognized and appreciated by one skilled in the art. See, e.g., U.S. Patent No. 4,663,334; European Patent Application 171209; Korn, et al., J. Pharm. Set, 69(9):1010- 13, 1980 and references cited below in the Preparations section for representative and/or analogous procedures for preparing the epoxides of formula II and IN. To illustrate, epoxides of formula II, where X is OCH2 or SCH2, may be prepared according to the procedure detailed in Scheme 3 wherein R 19 is OH or SH and X' is OCH2 or SCH2. Scheme 3
  • Epoxides 1-21 and 23-30 are prepared as described below for use as described in Scheme 1.
  • Epoxide 22 and 31 are prepared as described below for use as described in Scheme 2. These epoxides are pictured below in Table 1. Table 1
  • Epoxide 12 is prepared from 2-methoxyphenylboronic acid and 2-bromo-5- fluorothiophene; by a procedure substantially similar to that described for Epoxide 30.
  • the protected product from above is demethylated with pyridine hydrochloride neat at 200 degrees for 3 hours.
  • the reaction is poured into ice/water and ethyl acetate is added.
  • the layers are separated and the organic layer is washed with water, dried over sodium sulfate and concentrated.
  • the resulting residue is flash chromatographed with ethyl acetate/hexanes to afford 3-hydroxy-2-(thien-2-yl)pyridine (77%).
  • 3-Hydroxy-2- (thien-2-yl)pyridine is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
  • Epoxide 14 is prepared from 2-(3-methylisoxazol-5-yl)phenol (J. Org. Chem. 49:4419, 1984) and (2S)-glycidyl 3-nitrobenzenesulfonate by a procedure substantially similar to that described for Epoxide 1.
  • Epoxides 16-20 are prepared by a procedure substantially similar to that described for Epoxide 15.
  • the starting halogeno thiophenes used to prepare Epoxides 15-20 are known from the literature, see e.g., J. Mater. Chem., 5(4), 653-61, 1995; J. Chem. Soc, Perkin Trans. 2, 5:625-30, 1982; Chem. Ser., 5(5), 217-26, 1974; Bull. Soc. Chim. Fr., 11:4115-20, 1967; Bull. Soc. Chim. Fr., 11:4121-6, 1967; Bull. Inst. Chem. Res., 52(3):561-5, 1974; J. Med. Chem., 43(16):3168-3185, 2000; Bioorg. Med. Chem. Lett., 10(5):415-418, 2000; and JP 08311060.
  • Epoxide 21
  • 2-Thienyl-l-methoxybenzene (10 g, 53 mmol) is cooled to -78°C in dry tetrahydrofuran (265 ml) under nitrogen while stirring.
  • n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and the resulting mixture is stirred cold for an hour.
  • Chloromethyl formate (4.1 ml, 53 mmol, 1.0 eq.) is added and the reaction is stirred cold for another hour. The mixture is allowed to warm to room temperature before quenching with saturated bicarbonate solution and ethyl acetate.
  • the reaction is cooled and concentrated, taken up in chloroform, washed with 2N aqueous hydrochloric acid and water. The organic layer is dried over sodium sulfate and concentrated. The product residue is crystallized from hot ethyl acetate.
  • the product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol (180 ml) and the resulting mixture is heated to reflux. The reaction is allowed to stir for 18 hours before cooling and concentrating.
  • 2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved in dimethylformamide (100 mL) and water (25 mL) and cooled in ice.
  • Sodium hydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and the solution is warmed to ambient temperature. After thirty minutes, iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirred for 15 hours then diluted with ethyl acetate (300 mL) and water (500 mL).
  • the aqueous layer is washed three times with ethyl acetate (300 mL) and the organic layers are combined, washed three times with water (1 L), once with brine (1.2 L), dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the solid is purified by flash column chromatography (80% hexane:20% ethyl acetate gradient to 50%> hexane:50% ethyl acetate as an eluent) to give 23.5 g of 2-(l-methyltetrazol-3-yl)phenol (66%>).
  • the solid is purified by flash column cliromatography (80%> hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as an eluent) to give 270 mg (75%>) of the title epoxide.
  • FDMS m/e 233 (M++1).
  • the reaction is cooled, diluted with ethyl acetate, washed with brine, and the brine back extracted with ethyl acetate.
  • the extracts are combined, washed with aqueous NaHCO 3 , brine, dried (Na SO ), filtered, and the filtrate is concentrated.
  • the residue is purified by cliromatography (SiO , ethyl acetate/hexane gradient) to give 943 mg (70%>) of 5-(2-methoxyphenyl)thiophene-2- sulfonamide.
  • Amines 1-88 are prepared as described below or are obtained from commercial sources for use as described in Schemes 1 or 2. These amines are pictured below in Table
  • a mixture of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (25.0 g, 77.1 mmol), Raney Nickel ® (9.5 g wet lump), and 3A ethanol (250 mL) is pressurized to 50 psig with H and is heated to 60°C. After 1 hour, the mixture is cooled to ambient temperature. The mixture is diluted with tetrahydrofuran (100 mL) and is warmed to 50°C. The catalyst is removed by filtration and the cake is rinsed with 50°C tetrahydrofuran (4 x 50 mL).
  • Solid di-tert-butyl dicarbonate (20 g, 92 mmol) is added to a slurry of 2-methyl-l- [7-(benzyloxy)indol-3-yl]prop-2-ylamine (31.54 g, 107.1 mmol), triethylamine (16.5 mL, 118 mmol) and CH 2 C1 2 (300 mL) at ambient temperature; within 2 hours the slurry became a homogeneous solution. After 23.5 hours, the solution is poured into water (200 mL), and the layers are separated. The organic layer is extracted with 0.5 NaHSO 4 (200 mL), and the combined aqueous layers are rinsed with CH C1 2 (125 mL).
  • trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2- methyl-propyl)-lH-indol-7-yl ester (262 mg, 0.600 mmol) in dimethylformamide (3.5 mL) is added triethylamine (0.11 mL, 0.780 mmol), tetrakis(triphenylphosphine)- palladium (28 mg, 0.0240 mmol) and 2,4-bistrifluoromethylbenzeneboronic acid (201 mg, 0.780 mmol).
  • the mixture is heated to 100°C for 20 hours, then cooled, diluted with brine and ethyl acetate.
  • Phosphorous oxychloride (252 mL, 2.7 mol) is added dropwise over 15 minutes to precooled dimethylformamide (-10°C) (1800 mL) while maintaining the temperature below -5°C and the resulting solution is stirred for 1 hour at -10 to 0°C.
  • a solution of 7- benzyloxyindole (502 g, 2.25 mmol) in dimethylformamide (900 mL) is added dropwise while maintaining the temperature below 0°C. The cooling is removed and the resulting mixture is allowed to warm to room temperature and stir for 1 hour. After cooling to 0°C, 5 N NaOH (4.5 L) is added over 20 minutes at 0°C to 5°C. The resulting mixture is heated at reflux for 30 minutes.
  • the crude aldehyde from above (570 g, 2.25 mol), ammonium acetate (173.4, 2.25 mol) and nitroethane (661.8 g, 8.8 mol) are added to xylenes (1.35 L).
  • the heterogeneous mixture is heated at reflux under a Dean-Stark trap with 4A molecular sieves in the sleeve for 30 minutes without reflux return and 45 minutes with reflux return to remove water.
  • the reaction is complete the mixture is cooled to room temperature over 1 hour and is then cooled to 0°C for 30 minutes.
  • the solid product is collected by filtration and is washed sequentially with xylenes (1 L), water (1 L), and xylenes (1 L).
  • reaction mixture When the addition is complete, the reaction mixture is allowed to warm to 30°C over 1.5 hours and is stirred at 25°C to 35°C for 2 hours. To cpmplete the reaction, the mixture is heated to 60°C for 30 minutes. After cooling to 0°C, the reaction is quenched by the sequential addition of water (30 mL), 5 N NaOH (30 mL), and water (100 mL) and the resulting mixture is stirred over the weekend. The aluminum salts are removed by filtration and the cake rinsed with tetrahydrofuran (500 mL). The combined filtrates are concentrated to give 47.6 g (55% purity corrected yield, approx 65% pure) of 7-benzyloxy-3-(2-aminopropyl)-lH-indole.
  • the crude product is purified by flash chromatography (500 g silica gel, eluted with 8 x 500 mL dichloromethane, 4 x 500 mL 5% ethyl acetate/dichloromethane, 6 x 500 mL 10% ethyl acetate/dichloromethane).
  • the fractions containing product are concentrated and hexane is added to the solution to precipitate out the product affording 23.7 g (70.2%) yield) of racemic ⁇ l-methyl-2-[7-cyanomethoxy-lH- indol-3-yl]ethyl ⁇ -carbamic acid tert-butyl ester.
  • Amine 8b is prepared from (S)- ⁇ l-methyl-2-[7- cyanomethoxy-1 H-indol-3 -yl] ethyl ⁇ -carbamic acid tert-butyl ester by a procedure substantially similar to that described for amine 8a.
  • Amine 11 is prepared according to the literature procedure detailed in J. Med. Chem., 23:285-289, 1980.
  • the title amines are prepared from [2-(7-hydroxy-lH-indol-3-yl)- 1,1 -dimethyl- ethyl] -carbamic acid tert-butyl ester and 2-chloro-isonicotinonitrile and [2-(7-hydroxy- lH-indol-3-yl)-l,l-dimethyl-ethyl]-carbamic acid tert-butyl ester and 6-chloro- nicotinonitrile, respectively, as described for the preparation of Amine 12.
  • Boc-L-alanine 5 g, 24.4 mmol
  • indoline 3.2 ml, 29 mmol
  • N,N-diisopropylethylamine 9.2 mL, 53 mmol
  • dimethylformamide 130 mL
  • the title amine is prepared from Boc-D-alanine (5 g, 24.4 mmol) and indoline (3.2 ml, 29 mmol) by a procedure substantially similar to that described above for Amine 20.
  • Trifluoro-methanesulfonic acid 3 -(2-tert-butoxycarbonylamino-2-methyl-propyl)- lH-indol-7-yl ester 200 mg, 0.46 mmol
  • methyl acrylate 80 mg, 0.92 mmol
  • triethylamine 0.40 mL, 3.0 mmol
  • Dichlorobis(triphenylphosphine)palladium 31 mg, 0.045 mmol
  • the reaction mixture is heated to 90°C and allowed to stir overnight.
  • 3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-lH-indol-7-yl]-propionic acid methyl ester is prepared from 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-lH- indol-7-yl] -acrylic acid methyl ester as described below for the preparation of ⁇ 2-[7-(2- methanesulfonyl-ethyl)-lH-indol-3-yl]-l,l-dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester
  • the title amine is prepared from ⁇ 2-[7-(2-carbamoyl-ethyl)-lH-indol-3-yl]-l,l- dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of
  • the title amine is prepared from ⁇ 2-[7-(2-Cyano-vinyl)-lH-indol-3-yl]-l,l- dimethyl-ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of
  • ⁇ 1,1 -Dimethyl-2-[7-(2-[ 1 ,2,4]triazol- 1 -yl-vinyl)- lH-indol-3-yl]-ethyl ⁇ -carbamic acid tert-butyl ester is prepared from [l,l-dimethyl-2-(7-trifluoromethanesulfonylmethyl- lH-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 1 -vinyl- 1,2,4-triazole as described for the preparation of Amine 23 (93%).
  • FDMS m/e 381.2 (M + +1).
  • the title amine is prepared from ⁇ l,l-dimethyl-2-[7-(2-[l,2,4]triazol-l-yl-vinyl)- 1 H-indol-3 -yl] -ethyl ⁇ -carbamic acid tert-butyl ester as described for the alternate preparation of Amine 6 (56%).
  • FDMS m/e 282.2 (M+ +1).
  • Fresh sodium ethoxide is prepared by carefully adding NaH (16 g of 60% oil dispersion, 400 mmol) to 550 mL of ethanol under N 2 .
  • 2-(Trimethylsilylethynyl)-4,6- difluoro-N-carbethoxyaniline (28 g, 100 mmol) in 150 mL of ethanol is added and reaction is stirred at room temperature approximately 45 minutes, while monitoring by TLC (20%) ethyl acetate/hexane, UN) until all the starting material is consumed.
  • the mixture is heated to reflux and monitored by TLC until the intermediate material is consumed (approx. 1 hour).
  • Reaction is cooled to room temperature, concentrated, diethylether is added, washed with H 2 O, brine, dried ( ⁇ a 2 SO ), filtered, concentrated ; , and is purified by flash cliromatography (SiO 2 , ethyl acetate/hexane gradient) to yield 12 g of 5,7-difluoro-indole (78%).
  • the crude 3-iodo-5,7- difluoroindole is stirred in toluene (85 ml) and 5 N NaOH (70 ml), tetrabutylammonium bromide (1.25 g, 3.9 mmol), then benzenesulfonyl chloride (6.2 ml, 48 mmol) are added and the resulting mixture is stirred 24 hours.
  • the two phase reaction mixture is diluted with toluene, washed with brine, dried(Na 2 SO 4 ), filtered, concentrated and the residue is triturated with diethyl ether/petroleum ether.
  • Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise to a dioxane/tetrahydrofuran (90 ml/10 ml) solution of 2-(N,N-dibenzylamino)-l-(l- benzenesulfonyl-5,7-difluoro-lH-indol-3-yl)-propan-l-ol (1.9 g, 3.3 mmol) under N 2 at 0°C. After the addition is complete, the reaction is allowed to warm to room temperature, then is refluxed for 1 hour.
  • LAH Lithium aluminum hydride
  • reaction is quenched with cold aqueous NaHCO 3 , xtracted with ethyl acetate, washed with brine, dried (Na SO ), filtered, concentrated and is purified by flash chromatography (SiO 2 , ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro- 1 -methyl- 1 H-indol-3-yl)- 1 (R)-methyl-ethyl] -amine (89%).
  • a 45 ml tetrahydro solution of 6-fluoro-5-methoxy-3-(2-nitro-propenyl)-lH-indole (2.83 g, 11,3 mmol) is added dropwise to a 60 ml tetrahydrofuran suspension of LAH (2.14 g, 56.5 mmol) at 0°C, and the resulting mixture is allowed to warm to room temperature, then is refluxed for 1 hour.
  • reaction is quenched with H 2 O and 15% aqueous NaOH, then is filtered, concentrated, and the filtrate is diluted with ethyl acetate, washed with brine, dried (Na 2 SO 4 ), filtered, concentrated, and the residue is purified by flash cliromatography (90:10:1 CH 2 Cl 2 /methanol/NH OH) to give 1 g of the title amine (41%).
  • the combined organic extracts are washed with brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo.
  • the crude azide is dissolved in 25 ml of tetrahydrofuran and treated with triphenylphosphine (2.56 g, 9.78 mmol). After stirring at room temperature for 1 hour, the reaction mixture is heated at 60°C for 3 hours. Water (10 ml) is added to hydrolyze the intermediate aza-ylide and heating is continued for an additional 3 hours. Upon cooling to ambient temperature, the reaction mixture is diluted with ethyl acetate (200 ml) and brine (200 ml).
  • the title amines are prepared from 5-hydroxyindole, 4-hydroxy-2-methylindole, indole and 6-hydroxyindole, respectively, substantially as described for Amine 39.
  • Amine 50 is prepared from 5-fluoro-3-(dimethylaminomethyl)-lH-indole in a method similar to that described for the preparation of Amine 49.
  • Methyl indole-4-carboxylate (7.0 g, 40 mmol) and Eschenmoser's salt (N,N- dimethylmethyleneammonium iodide; 7.8 g, 42 mmol) are combined in 130 ml of acetic acid. After heating at 65 °C for 2 hours, the reaction mixture is concentrated in vacuo. The resulting solid is triturated with ethyl acetate, filtered and dried in vacuo to give 3- dimethylaminomethyl-lH-indole-4-carboxylic acid methyl ester hydroiodide in quantitative yield.
  • 6-Fluoro-3-(2-methyl-2-nitropropyl)-lH-indole is prepared from 6-fluoro ⁇ 3- (dimethylaminomethyl)-lH-indole by a method similar to that described for Amine 49, paragraph 1.
  • a solution of 6-fluoro-3-(2-methyl-2-nitropropyl)-lH-indole (1.16 g, 4.91 mmol) in 6 ml of tetrahydrofuran and 12 ml of methanol is treated with CuSO 4 -5 ⁇ 2 O (400 mg, 1.35 mmol) andNaBH 4 (882 mg, 23.3 mmol).
  • 6-Benzyloxyindole-3-carboxaldehyde is converted to 2-(6-benzyloxy-lH-indoyl-3- yl)-l,l-dimethylethylamine by sequentially following the procedures detailed for Amine 61, 1 st paragraph, then for Amine 57, 1 st and 2 nd paragraphs.
  • the BOC protected amine is deprotected substantially as described for Amine 6 to give the title amine 58 in 66% yield.
  • Amine 60 is prepared from 7-fluoroindole by sequentially following the methods described for Amine 51, 1 st paragraph; Amine 49, 1 st paragraph; and Amine 51, 3 rd paragraph.
  • the title amines are prepared from methyl indole-5 -carboxylate, 5-cyanoindole, methyl indole-7-carboxylate, 6-cyanoindole and 4-cyanoindole, respectively, in a method similar to that described for the preparation of Amine 51.
  • Amine 63 is prepared from Amine 62 in 61% yield by essentially following the procedure described for Amine 53.
  • the title amines are prepared from trifluoro-methanesulfonic acid 3-(2-tert- butoxycarbonylamino-2-methyl-propyl)-lH-indol-7-yl ester and: 4- methoxycarbonylbenzeneboronic acid; 4-acetamidylbenzeneboronic acid; 3- methoxycarbonylbenzeboronic acid; and 5-methoxycaronylthiophen-2-ylboronic acid, respectively, using the procedure described for the preparation of Amine 2.
  • ⁇ 1,1 -Dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)- lH-indol-3-yl]-ethyl ⁇ -carbamic acid tert-butyl ester is prepared from [l,l-dimethyl-2-(7-trifluoromethanesulfonylmethyl-lH- indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 2-vinylpyrazine as described for the preparation of Amine 23 (99%).
  • FDMS m/e 393.2 (M+ +1)
  • Trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)- lH-indol-6-yl ester is prepared from 6-benzyloxy gramine and 2-nitropropane as described in the preparation of Amine 1, l st -5 th paragraphs.
  • Trifluoromethanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-lH-indol-6-yl ester and acrylonitrile are reacted and the Boc-protecting group is removed from the resulting product as described in the prepararation of Amine 23 to give the title amine (75%).
  • the 7-nitroindole (20.0 g, 123.3 mmol) and Eschenmoser's salt (24.0 g, 129.5 mmol) are suspended in glacial acetic acid (500 mL) and stirred at 65 °C for 1 hour. The reaction mixture is cooled and the resulting solid filtered, and washed with ethyl acetate (2 x 50 mL). This solid is then dried in a vacuum oven overnight to yield 39.3 g of the desired 7-nitrogramine hydroiodide salt (89.4%o).
  • the 7-nitrogramine salt (2.0 g, 5.8 mmol) is suspended in a mixture of 2- nitropropane (9.5 mL) and methanol (9.5 mL).
  • 3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolved in ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture is stirred under a balloon of nitrogen for 2-3 hours. The mixture is filtered to remove the Pd/C, and the filtrate is evaporated to give a crude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole is immediately dissolved in pyridine (100 mL) and the solution is cooled with an ice bath to 0°C. Benzenesulfonyl chloride is added slowly, and the mixture is stirred for 5 minutes at this temperature before removing the ice bath.
  • the reaction mixture is stirred overnight before being quenched by addition of IN HCl and ethyl acetate.
  • the aqueous layer is extracted with ethyl acetate several times and the combined organic extracts are washed twice with brine and dried over Na 2 SO 4 to give a crude oil.
  • the crude material is purified by flash cliromatography (25%> ethyl acetate/hexanes) to provide 1.9 g of 3-(2-nitro-2- methylpropyl)-7-benzenesulfonamidyl-indole (71 %).
  • 3-(2-Nitro-2-methylpropyl)-7-methanesulfonamidyl-indole is prepared from crude 3-(2-nitro-2-methylpropyl)-7-aminoindole and methanesulfonyl chloride and 3-(2-nitro-2- methylpropyl)-7-methanesulfonamidyl-indole is converted to the title amine by the procedure described for Amine 77 (2.3 g).
  • the Boc-protected title amine is prepared from Boc- ⁇ -methylalanine and indoline by the procedure described above for Amine 20 except that the reaction is conducted in dichloromethane and the crude Boc-protected amine is purified by normal phase flash chromatography (silica gel, 20-60%» ethyl acetate/hexanes).
  • the mixture is cooled to room temperature, and trifluoro-methansulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl- propyl)-lH-indol-7-yl ester (0.8 equivalents), l,l'-bis(diphenylphosphino) ferrocene)palladium(H)dichloride-dichlormethane (0.03 equivalents) and 2M Na 2 CO 3 (5 equivalents) are added under argon. The resulting mixture is heated to 80°C and then allowed to stir overnight at this temperature. The mixture is diluted with water and extracted with ethyl acetate or CH 2 C1 2 .
  • the Boc-protected amine is dissolved in 5N HCl in isopropanol (5 ml/mmol) and stirred overnight at room temperature. The mixture is evaporated, dissolved in ethanol and loaded onto a 5 g SCX column conditioned with methanol. The column is washed twice with 5 ml ethanol to remove impurities. The title compound is then eluted with 5 ml ethanolic NH 3 and 5 ml ethanol. Evaporation of the solvent gives the deprotected amine.
  • the title amines are prepared from trifluoro-methansulfonic acid 3-(2-tert- butoxycarbonylamino-2-methyl-propyl)-lH-indol-7-yl ester and: ethyl 3-bromobenzoate; 3'-bromoacetophenone; and 4'-bromoacetophenone, respectively, using the procedure described for the preparation of Amine 81.
  • Amine 85 is prepared by hydrolysis of the methyl ester of Amine 62 by essentially following the procedure detailed for Amine 86.
  • Amine 86 A solution Amine 61 (2 g, 8.12 mmol) in 24 ml of tetrahydrofuran and 8 ml of MeOH is treated with IM aqueous LiOH (8.1 ml). The resulting mixture is heated overnight at 60 °C. An additional portion of IM aqueous LiOH (2 ml) is added and heating is continued for 24 hours to drive the hydrolysis to completion. The reaction mixture is concentrated in vacuo to give the crude lithium salt as a white solid.
  • Amine 88 is prepared from indole-2-carboxylic acid and l,2-diamino-2- methylpropane by essentially following the procedure detailed for Amine 55.
  • the title compound is prepared from Epoxide 31 and Amine 6 as described above for Aryl Halide 1.
  • the title compound is prepared from Epoxide 31 and Amine 11 as described above for Aryl Halide 1.
  • a stirred mixture of an epoxide of formula II (1 equivalent) and an amine of formula III (1-2 equivalents) in ethanol, methanol, n-butanol or t-butanol is heated at 70- 80°C for 2-72 hours.
  • the solvent is evaporated to dryness to give a crude oil that is optionally diluted with methanol or ethanol and passed over a cation exchange column (eluting the free base product with IN methanolic ammonia) before further purification.
  • the final products prepared via Representative Procedure 1 or 2 may be further purified by flash or radial cliromatography.
  • Typical cliromatography conditions include: a) using a variable mixture of 25:5:1 chloroform/methanol/ammonium hydroxide and 9:1 chloroform/methanol; b) a variable mixture of 90:10:1 CH 2 Cl 2 /ethanolic NH 3 gradient; c) dichloromethane/6-12%) methanol, 0.15-0.35M ammonia in dichloromethane gradient; d) methylene chloride with a step gradient to 2-8%) methanol; e) chloroform/2.0M ammonia in methanol, from 0-10%> to 6-20% gradient elution or f) isocratic 6-8%> 2M ammonia in methanol: 92-94% dichloromethane.
  • the final products maybe purified on C18 bonded silica gel using either mass guided or UN guided reverse phase liquid chromatography (acetonitrile/water with 0.01 % hydrochloric acid or 0.1 % trifluoroacetic acid).
  • the free base thus prepared may be salified, e.g., by dissolution of the free base in CH2CI2 or diethylether, adding IM ethanolic HCl or a solution of HCl in diethylether, and evaporating the volatiles, or as described in more detail below.
  • a hydrochloride salt may be prepared by dissolving the free base in dichloromethane, diethylether, or a mixture of ethyl acetate and methanol and adding IM ethanolic HCl, a solution of HCl in diethylether, or 0.5M ammonium chloride. The resulting mixture is allowed to stir for a short time, e.g., for five minutes, before evaporating the volatiles and optionally triturating in diethyl ether to give the hydrochloride salt.
  • the oxalate salts may be prepared by dissolving the free base in a small amount of ethyl acetate, optionally adding methanol for solubitity. The resulting solution is treated with 1 equivalent of a 0.5M solution of oxalic acid in ethyl acetate. The reaction mixture is either concentrated in vacuo or centrifuged, separated, and the solids are dried, to give the oxalate salt.
  • the free base may be dissolved in a small amount of ethyl acetate or methanol and then treated with 1 equivalent of succinic acid in methanol.
  • the resulting slurry is dissolved in the minimum amount of methanol then concentrated in vacuo to give the succinate salt.
  • Amine 6 (12.08 g, 43.2 mmol, 1.10 equivalents) is dissolved in acetonitrile (86 mL) containing N-(trimethylsilyl)acetamide (95%) pure, 5.1 g, 39.2 mmol, 1.0 equivalent - warmed to effect dissolution).
  • Epoxide 3 is then added (8.0 g, 96% pure, 1.0 equivalent) and the solution is allowed to stand at 24-26°C for 45 hours after which water (10 mL) and acetic acid (6.3 g) are added. After 1.5 hours, the bulk of the solvents are removed under vacuum (25 °C, 10 mm, 16 hours).
  • Epoxide 1 (232 mg, 1 mmol), Amine 33 (255 mg, 1.1 mmol), and ytterbium trifluoromethane sulfonate hydrate (62 mg, 0.1 mmol) in 10 ml acetonitrile are reacted and purified as in Example 194 to give 92 mg of the free base of the title compound (20%)).
  • a 5 ml methanol solution of the free base (92 mg, 0.2 mmol) and NH 4 C1 (11 mg, 0.2 mmol) is stirred for 5 minutes at room temperature, concentrated, triturated in diethylether, filtered, and dried to give 95 mg of the title compound.
  • Racemic Amine 45 and Epoxide 1 are coupled in a fashion similar to that described in Representative Procedure 2 to give a mixture of the free bases of the title compounds.
  • the title compounds are separated, one from the other, by normal phase chiral HPLC (Chiralpak AD; 15%) 3 A ethanol in heptane with 0.2%o dimethylethylamine) to give the free base of Example 200 (faster eluting) in 40% yield and the free base of Example 201 in 35%o yield.
  • the oxalate salts are prepared by separately dissolving each of the free base isomers in a small amount of ethyl acetate, optionally adding methanol for solubility.
  • Epoxide 3 is reacted with Amine 7 according to the Representative Procedure 2.
  • the crude amination mixture (290 mg) is dissolved in 10 ml ethanol, 2M NaOH (2 ml) is added and the resulting mixture is left to stir at room temperature overnight.
  • the solution is neutralized with acetic acid and loaded on a SCX column. After washing with ethanol, the product is eluted with 10%> NH 3 in ethanol.
  • the fractions containing product are combined and evaporated to yield 220 mg of the title compound (80%).
  • Emax (SEM) 73.8 (8.0).
  • a compound of formula N (6.4 mmol) is dissolved in 50 ml of dry dioxane and thoroughly flushed with argon. Palladium(O) tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under argon and stirred at ambient temperature until the mixture becomes homogenous. The clear solution is divided into aliquots of 2 ml, and each testing tube is charged with 2 equivalents of an aryl boronic acid and 500 microliters of 2M aqueous sodium carbonate under argon. The testing tubes are sealed and heated in a microwave oven (MLS ETHOS 1600) for 35 minutes and 100°C at 1000W.
  • MLS ETHOS 1600 microwave oven
  • the final products prepared via Suzuki coupling may be purified by normal phase chromatography (silica gel, dichloromethane/ethanolic ammonia) providing the free bases or by reverse phase chromatography (acetonitrile/0.1 % trifluoroacetic acid or 0.01 % HCl in water) providing the trifluoro acetate or hydrochloride salts.
  • the final products existing as salts may also be prepared in a separate salification step by dissolution of the free base in ethanol or dichloromethane and treatment of the solution with acid, e.g., IN ethanolic HCl. Removal of all volatiles under reduced pressure, affords the desired salt.
  • the table below sets out representative combinations of aryl halides and boronic acids that are reacted as described above in Representative Procedure 5(a) or 5(b).
  • Potassium carbonate 14 mg is added to 2 mL of dimethylsulfoxide.
  • the mixture is stirred under nitrogen, and heated to 50 C for 30 minutes.
  • the mixture is cooled to room temperature, and the compound of Example 115 (27 mg) dissolved in 2 mL of dimethylsulfoxide is added to the mixture, followed by the addition of 0.5 mL of water dropwise.
  • the mixture is allowed to stir for 10 to 15 minutes, then 0.1 mL of 30%> hydrogen peroxide is added dropwise. After 20 minutes, 15 mL of saturated aqueous sodium sulfite solution and 5 mL water is added and the mixture is extracted 3 times with 40 mL of ethyl acetate.
  • Example 222 The crude residue containing the compound of Example 124 is dissolved in tetrahydrofuran and 1.2 equivalents of lithium hydroxide is added. The reaction mixture is stirred at ambient temperature overnight. The reaction is concentrated, and purified on C 18 bonded silica gel using reverse phase liquid chromatography (acetonitrile/water with 0.1% trifluoroacetic acid). FDMS m/e 465.2.
  • Example 222
  • the title compound is prepared from the compound of Example 137 (200 mg, 0.43 mmol) by a procedure substantially similar to that described for Example 223 to give 50 mg of the title compound (85%).
  • FDMS m/e 495.2 (M + +1).
  • Example 229 The title compound is prepared from the compound of Example 145 by a procedure substantially similar to that described for the preparation of Example 227.
  • FDMS m/e 493.1 (M + +1).
  • Example 229
  • the free base of the title compound is prepared from the compound of Example 143 (76 mg, 0.16 mmol) and azidotrimethylsilane (190 mg, 1.62 mmol) by a procedure substantially analogous to that described in Example 229 to give the title compound.
  • Example 144 The title compound is prepared from the compound of Example 144 and azidotrimethylsilane by a procedure substantially analogous to that described in Example
  • the title compounds are separately prepared from the compound of Examples 24, 151, 168 and 169, respectively, in a manner similar to that described in Example 233.
  • the title compounds are separately prepared by hydrolysis of crude free base of the product from Examples 70, 75 and 76, respectively, in a method similar to that detailed in Example 238.
  • the title compound is prepared in 54% yield by hydrolysis of the free base of the compound of Example 154 with LiOH in a manner similar to that described in Example 242.
  • Example 116 The compound of Example 116 (97 mg) is dissolved in 6 mL of methanol. Sodium hydroxide (2N, 3 mL) is added and the mixture is refluxed for 16 hours. Water
  • the aqueous mixture is extracted with ethyl acetate (3 x 50 mL).
  • the combined organic extracts are dried with anhydrous sodium sulfate, filtered, and the solvent is evaporated.
  • the crude title compound is prepared from he compound of Example 116 (97 mg) via the procedure described in Example 219.
  • FDMS m/e 542 (M + +l of free base).
  • Example 178 To a solution of the compound of Example 178 (103 mg, 0.186 mmol) in methanol (5mL) is added sodium hydroxide (0.93 mL, 2M, 1.86 mmol). The mixture is refluxed for 4 hours then diluted with HCl and extracted three times with ethyl acetate.
  • Example 182 The compound of Example 182 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (57%>).
  • FDMS m/e 526 (M++1 of free base).
  • Example 180 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (88%>).
  • FDMS m/e 541 (M + +l of free base).
  • Example 184 The compound of Example 184 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 (32%).
  • FDMS m e 526 (M + +l of free base).
  • Example 181 is converted to the title compound via the procedure described for the preparation of the compound of Example 246 except that chromatography on the crude free base is not performed, histead, the crude free base is dissolved in a small amount of ethyl acetate and treated with 1 equivalent of succinic acid in methanol. The resulting slurry is dissolved in the minimum amount of methanol then concentrated in vacuo to give the title compound (78%).
  • FDMS m/e 547 (M + +l of free base).
  • Example 2 The compound of Example 1 (8.87 g, 18.8 g, 1.00 equivalent) is treated all at once with concentrated HCl (1.57 mL, 0.95 equivalents) in ethyl acetate (221 mL, 25 °C). The ethyl acetate is evaporated under vacuum and the solid stirred with 250 mL of diethyl ether (3 hours) after which the mixture is filtered and the resulting solid dried under a stream of nitrogen to afford 8.98 g of the title compound (93%>). MS: 459.2.
  • Example 216 To a solution of the compound of Example 216 in dry ethanol is added 10%> HCl in ethanol and the mixture is stirred at room temperature. The solvent is evaporated, the residue re-dissolved in ethanol and loaded on a SCX column. After washing with ethanol, the products are eluted with 10%> NH 3 in ethanol, evaporated, separated and purified via preparative HPLC (Cl 8 bonded silica gel reverse phase liquid chromatography (acetonitrile/water with 0.1 %> trifluoroacetic acid) to give the title compounds.
  • preparative HPLC Cl 8 bonded silica gel reverse phase liquid chromatography (acetonitrile/water with 0.1 %> trifluoroacetic acid) to give the title compounds.
  • Cells from each of the above cell lines are resuspended and added (20,000/well) to a 96-well plate. Cells are incubated at 37°C with representative compounds of the invention for 20 minutes in buffer (Hank's balanced salt solution, 10 mM HEPES, 0.1%> BSA, 1 mM L-ascorbic acid, 0.2%o dimethyl sulfoxide, 1 mM 3-isobutyl-l- methylxanthine, pH 7.4).
  • buffer Hort's balanced salt solution, 10 mM HEPES, 0.1%> BSA, 1 mM L-ascorbic acid, 0.2%o dimethyl sulfoxide, 1 mM 3-isobutyl-l- methylxanthine, pH 7.4
  • c-AMP level is quantified by scintillation proximity assay (SPA) using a modification of the commercially available c-AMP kit (Amersham, Arlington Heights, IL) with rabbit anti-cAMP antibody (ICN Biomedicals, Aurora, Ohio) for the kit.
  • quench buffer 50 mM Na Acetate, 0.25% Triton X-100, pH 5.8
  • SPA scintillation proximity assay
  • Isoproterenol is accepted in the art as a non-selective ⁇ agonist and is widely used as a comparator in evaluating the activity of compounds. See Trends in Pharm. Sci. , 15:3, 1994.
  • the % intrinsic activity (Emax) of representative compounds of the invention is assessed relative to isoproterenol by the compound's maximal response divided by the isoproterenol maximal response times 100.
  • the salts of the present invention are useful in treating conditions in human and non-human animals in which the ⁇ receptor has been demonstrated to play a role.
  • the diseases, disorders or conditions for which compounds of the present invention are useful in treating include, but are not limited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia, (7) atherosclerosis of coronary, cerebrovascular and peripheral arteries, (8) hypertension, (9) disorders of the gall bladder including acute and chronic cholecystitis, (10) depression, (11) elevated intra-ocular pressure and glaucoma, (12) nonspecific diarrhea dumping syndrome, (13) hepatic steatosis [fatty degeneration of the liver], and obesity dependent diseases/disorders such as: (14) gastrointestinal disorders including peptid ulcer, esophagitis, gastritis and duodenitis, (including that induced by H.
  • intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis and gastrointestinal ulcerations
  • irritable bowel syndrome and other disorders needing decreased gut motility (16) diabetic retinopathy, (17) neuropathic bladder dysfunction, (18) osteoarthritis, (19) restrictive lung disease, (20) obstructive sleep apnea, (21) congestive heart failure, (22) venous stasis and skin disorders related to venous stasis, (23) decreased libido (in both males and females), and (24) acute and clironic cystitis.
  • obesity dependent means that the symptoms of said diseases will be ameliorated via the present salt's effect on the patient's weight.
  • BMI body mass index
  • a patient population at particular need of treatment are those with a BMI >30 or >27 with co-morbities.
  • Human patients in need of type 2 diabetes treatment are typically individuals with a BMI ⁇ 25 , . e. , individuals that are not overweight.
  • compositions of formula I are preferably formulated in a unit dosage form prior to administration. Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of formula I and a pharmaceutical carrier.
  • the present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient (formula I compound) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • Silicon dioxide fumed 10 - 650 Stearate acid 5 - 15
  • the components are blended and compressed to form tablets.
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • the solution of the above ingredients is intravenously administered to a patient at a rate of about 1 ml per minute.
  • Dose The specific dose administered is determined by the particular circumstances surrounding each situation. These circumstances include, the route of administration, the prior medical history of the recipient, the pathological condition or symptom being treated, the severity of the condition symptom being treated, and the age and sex of the recipient. However, it will be understood that the therapeutic dosage administered will be determined by the physician in the light of the relevant circumstances. Generally, an effective minimum daily dose of a compound of formula I is about 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about 500, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 15 mg and 60 mg. The exact dose may be determined, in accordance with the standard practice in the medical arts of "dose titrating" the recipient; that is, initially administering a low dose of the compound, and gradually increasing the does until the desired therapeutic effect is observed.
  • the compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes.
  • the compound of formula I may be used in combination with other drugs that are used in the treatment of the diseases or conditions for which the present salts are useful, e.g., treatment of obesity and/or type 2 diabetes.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical unit dosage form containing such other drugs in addition to the present salt is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un agoniste de récepteur β3 adrénergique correspondant à la formule (I); ou un sel pharmaceutiquement acceptable de celui-ci, capable d'augmenter la lipolyse et le transport d'énergie dans les cellules; de ce fait, il est utile pour traiter le diabète type 2 et/ou l'obésité.
PCT/US2002/021317 2001-08-14 2002-08-06 Agonistes de beta-3 adrenergiques WO2003016307A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/486,867 US7208505B2 (en) 2001-08-14 2002-08-06 β3 adrenergic agonists
DE60215028T DE60215028T2 (de) 2001-08-14 2002-08-06 Indol derivate als beta-3-adrenerge agonisten zur behandlung von typ 2 diabetes
JP2003521230A JP2005501856A (ja) 2001-08-14 2002-08-06 β３アドレナリン作動性アゴニスト
EP02752178A EP1421078B1 (fr) 2001-08-14 2002-08-06 Derives d'indole en tantqu'agonistes du recepteur beta-3 adrenergique pour le traitement du diabete type 2

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US31227501P 2001-08-14 2001-08-14
US60/312,275 2001-08-14

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WO2003016307A1 true WO2003016307A1 (fr) 2003-02-27

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JP (1) JP2005501856A (fr)
AT (1) ATE340794T1 (fr)
DE (1) DE60215028T2 (fr)
ES (1) ES2272749T3 (fr)
WO (1) WO2003016307A1 (fr)

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US7071208B2 (en) 2001-11-20 2006-07-04 Eli Lilly And Company β3 Adrenergic agonists
US7205407B2 (en) 2001-11-20 2007-04-17 Eli Lilly And Company 3-Substituted oxindole β3 agonists
US7208505B2 (en) 2001-08-14 2007-04-24 Eli Lilly And Company β3 adrenergic agonists
WO2007146717A3 (fr) * 2006-06-12 2008-03-27 Novartis Ag Procédé de fabrication des sels de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
JP2008509929A (ja) * 2004-08-13 2008-04-03 メタボレックス インコーポレーティッド Ｐｐａｒの調節剤およびそれらの調製法
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
US7612099B2 (en) 2005-12-01 2009-11-03 Hoffmann-La Roche Inc. Vinylogous acid derivatives
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

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US7208505B2 (en) 2001-08-14 2007-04-24 Eli Lilly And Company β3 adrenergic agonists
US7071208B2 (en) 2001-11-20 2006-07-04 Eli Lilly And Company β3 Adrenergic agonists
US7205407B2 (en) 2001-11-20 2007-04-17 Eli Lilly And Company 3-Substituted oxindole β3 agonists
US7241772B2 (en) 2001-11-20 2007-07-10 Eli Lilly And Company β3 adrenergic agonists
US7253181B2 (en) 2001-11-20 2007-08-07 Eli Lilly And Company β3 adrenergic agonists
US7265127B2 (en) 2001-11-20 2007-09-04 Eli Lilly And Company β3 adrenergic agonists
US7009060B2 (en) 2002-01-11 2006-03-07 Eli Lilly And Company 2-oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists
US7214697B2 (en) 2002-01-11 2007-05-08 Eli Lilly And Company 2-Oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
JP2008509929A (ja) * 2004-08-13 2008-04-03 メタボレックス インコーポレーティッド Ｐｐａｒの調節剤およびそれらの調製法
US7612099B2 (en) 2005-12-01 2009-11-03 Hoffmann-La Roche Inc. Vinylogous acid derivatives
US7989639B2 (en) 2006-06-12 2011-08-02 Novartis Ag Process for making salts of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide
WO2007146717A3 (fr) * 2006-06-12 2008-03-27 Novartis Ag Procédé de fabrication des sels de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
TWI385142B (zh) * 2006-06-12 2013-02-11 Novartis Ag 製造ｎ-羥基-３-〔４-〔〔〔２-（２-甲基-１ｈ-吲哚-３-基）乙基〕胺基〕甲基〕苯基〕-２ｅ-２-丙烯醯胺之鹽之方法
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques

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EP1421078A1 (fr) 2004-05-26
DE60215028T2 (de) 2007-03-15
US20050080110A1 (en) 2005-04-14
DE60215028D1 (de) 2006-11-09
EP1421078B1 (fr) 2006-09-27
ATE340794T1 (de) 2006-10-15
US7208505B2 (en) 2007-04-24
JP2005501856A (ja) 2005-01-20

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